{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:01:49Z","timestamp":1772236909538,"version":"3.50.1"},"posted":{"date-parts":[[2024,3,8]]},"group-title":"In Review","reference-count":56,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,12]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  <italic>OTULIN<\/italic>\n                  encodes an eponymous linear deubiquitinase (DUB), which through the regulation of M1-Ub dynamics, is essential for controlling inflammation as a negative regulator of the canonical NF-\ud835\udecbB signaling pathway. Biallelic loss-of-function (LOF) mutations in\n                  <italic>OTULIN<\/italic>\n                  cause an autosomal recessive condition named Otulin-Related Autoinflammatory Syndrome (ORAS), also known as Otulipenia or AutoInflammation, Panniculitis, and Dermatosis Syndrome (AIPDS). Monoallelic\n                  <italic>OTULIN<\/italic>\n                  LOF, also known as OTULIN Haploinsufficiency (OHI) or Immunodeficiency 107 (IMD107), has been linked to an incompletely penetrant, dominantly inherited susceptibility to invasive Staphylococcal infections. At the same time, a recent novel ORAS-like inflammatory syndrome was described in association with a heterozygous missense mutation that appears to exert dominant negative effects. In this manuscript, we report the identification of a novel homozygous missense mutation, c.595T&gt;A; p.(Trp199Arg), in a Moroccan infant with an ORAS phenotype. We go on to systematically review the literature for OTULIN-related human disease phenotypes by using the GenIA databaseto collect, extract and harmonize all clinical, laboratory and functional data for published patients and variants. Our comprehensive synthesis of genotypic, phenotypic, and mechanistic data enables a more in-depth view of the diverse mechanisms and pathways by which the\n                  <italic>OTULIN<\/italic>\n                  pathogenic variants may lead to human immune disease. This review may help variant classification activities and the drafting of diagnostic and management guidelines; but it also identifies outstanding knowledge gaps and raises additional questions for future investigation.\n                <\/p>","DOI":"10.21203\/rs.3.rs-3950863\/v2","type":"posted-content","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T14:44:32Z","timestamp":1709909072000},"source":"Crossref","is-referenced-by-count":1,"title":["OTULIN-related conditions: Report of a new case and review of the literature using GenIA"],"prefix":"10.21203","author":[{"given":"Andr\u00e9s","family":"Caballero-Oteyza","sequence":"first","affiliation":[{"name":"Cluster of Excellence \"RESIST - Resolving Infection Susceptibility\""}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Crisponi","sequence":"additional","affiliation":[{"name":"National Research Council"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao P.","family":"Peng","sequence":"additional","affiliation":[{"name":"Johns Hopkins University"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongying","family":"Wang","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavla","family":"Mrovecova","sequence":"additional","affiliation":[{"name":"University Medical Center Freiburg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Olla","sequence":"additional","affiliation":[{"name":"National Research Council"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Siguri","sequence":"additional","affiliation":[{"name":"National Research Council"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farida","family":"Marnissi","sequence":"additional","affiliation":[{"name":"University of Hassan II Casablanca"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zineb","family":"Jouhadi","sequence":"additional","affiliation":[{"name":"University of Hassan II Casablanca"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivona","family":"Aksentijevich","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bodo","family":"Grimbacher","sequence":"additional","affiliation":[{"name":"University Medical Center Freiburg"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Proietti","sequence":"additional","affiliation":[{"name":"Hannover Medical School"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fimmu.2019.00101","article-title":"Biochemistry of Autoinflammatory Diseases: Catalyzing Monogenic Disease","volume":"10","author":"Beck DB","year":"2019","unstructured":"Beck DB, Aksentijevich I. 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